The association of chronic hyperglycemia and the devastating long-term complications of diabetes was clearly established by the Diabetes Control and Complication Trial (DCCT) (The Diabetes Control and Complications Trial Research Group. “The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus” N Engl J Med 329: 978-986, 1993; Santiago J V “Lessons from the Diabetes Control and Complications Trial” Diabetes 1993, 42: 1549-1554).
The DCCT found that in patients receiving intensive insulin therapy, there was a reduced risk of 76% for diabetic retinopathy, 50% for diabetic nephropathy and 60% for diabetic neuropathy. The long-term benefits of tight glycemic control have been further substantiated by the Epidemiology of Diabetes Interventions and Complications study which found over a 50% reduced risk of macrovascular disease as a result of intensive insulin therapy (The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complication (DCCT/EDIC) Study Group, “Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes”, 353, 2643-2653, 2005).
However, the DCCT found that patients receiving intensive insulin therapy were at a threefold increased risk of severe hypoglycemia. Patients adhering to intensive insulin therapy regimens were found to have lowered thresholds for activation of neurogenic warning systems and consequently were at increased risk for more severe hypoglycemic events. (Amiel S A, Tamborlane W V, Simonson D C, Sherwin R S., “Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus.” N Engl J. Med. 1987 28; 316(22):1376-83).
The increased risk of hypoglycemia and the fear associated with patients' perception of that risk has been cited as the leading obstacle for patients to achieve the targeted glycemic levels (Cryer P E. “Hypoglycaemia: The limiting factor in the glycemic management of type I and type II diabetes” Diabetologia, 2002, 45: 937-948). In addition to the problem of chronic hyperglycemia contributing to long-term complications and the problem of acute iatrogenic hypoglycemia contributing to short-term complications, recent research suggests that transient episodes of hyperglycemia can lead to a wide range of serious medical problems besides previously identified microvascular complications as well as macrovascular complications such as increased risk for heart disease. (Haffner S “The importance of postprandial hyperglycemia in development of cardiovascular disease in people with diabetes” International Journal of Clinical Practice, 2001, Supplement 123: 24-26; Hanefeld M: “Postprandial hyperglycemia: noxious effects on the vessel wall” International Journal of Clinical Practice, 2002, Supplement 129: 45-50).
Additional research has found that glycemic variation and the associated oxidative stress may be implicated in the pathogenesis of diabetic complications (Hirsh I B, Brownlee M “Should minimal blood glucose variability become the gold standard of glycemic control?” J of Diabetes and Its Complications, 2005, 19: 178-181; Monnier, L., Mas, E., Ginet, C., Michel, F., Villon L, Cristol J-P, and Collette C, “Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes”. JAMA 2006, 295, 1681-1687). Glycemic variation has also been identified as a possible explanation for the increased prevalence of depression in both type 1 and type 2 diabetes (Van der Does F E. De Neeling J N, Snoek F J, Kostense P J, Grootenhuis P A, Bouter L M, and R J Heine: Symptoms and well-being in relation to glycemic control in type II diabetes Diabetes Care, 1996, 19: 204-210; De Sonnaville J J. Snoek F J. Colly L P. Deville W. Wijkel D. Heine R J: “Well-being and symptoms in relation to insulin therapy in type 2 diabetes” Diabetes Care, 1998, 21:919-24; Cox D J, Gonder-Frederick L A, McCall A, et al. “The effects of glucose fluctuation on cognitive function and QOL: the functional costs of hypoglycaemia and hyperglycaemia among adults with type 1 or type 2 diabetes” International Journal of Clinical Practice, 2002, Supplement 129: 20-26).
The potential benefits of continuous glucose monitoring have been recognized by numerous researchers in the field (Skyler J S “The economic burden of diabetes and the benefits of improved glycemic control: the potential role of a continuous glucose monitoring system” Diabetes Technol Ther 2 (Suppl 1): S7-S12, 2000; Tansey M J, Beck R W, Buckingham B A, Mauras N, Fiallo-Scharer R, Xing D, Kollman C, Tamborlane W V, Ruedy K J, “Accuracy of the modified Continuous Glucose Monitoring System (CGMS) sensor in an outpatient setting: results from a diabetes research in children network (DirecNet) study.” Diab. Tech. Ther. 7(1):109-14, 2005; Klonoff, D C: “Continuous glucose monitoring: Roadmap for 21st century diabetes therapy” Diabetes Care, 2005, 28: 1231:1239). Accurate and reliable real-time continuous glucose monitoring devices have the ability to alert patients of high or low blood sugars that might otherwise be undetected by episodic capillary blood glucose measurements.
Continuous glucose monitors have the potential to permit more successful adherence to intensive insulin therapy regimens and also to enable patients to reduce the frequency and extent of glycemic fluctuations. However, the development of this technology has proceeded more slowly than anticipated. For example, two recent comprehensive reviews of decades of research in the field cited the lack of accuracy and reliability as the major factor limiting the acceptance of this new technology as well as the development of an artificial pancreas (Chia, C. W. and Saudek, C. D., “Glucose sensors: toward closed loop insulin delivery” Endocrinol. Metab. Clin. N. Am., 33, 174-195, 2004; Hovorka, R. “Continuous glucose monitoring and closed-loop systems” Diabet. Med. 23, 1-12, 2006).
As continuous analyte monitoring becomes more prevalent, of use are continuous analyte sensors and systems that are accurate to such a high degree that confirmatory analyte measurement are not needed to verify the continuous sensing measurements, e.g., prior to a user relying on the continuous measurements. Also of interest are such sensors that work in concert with a drug delivery device.